Suspected oncologic adverse reactions associated with interleukin‐23 inhibitors in EudraVigilance: Comparative study and gender distribution

Abstract Psoriasis is a chronic inflammatory skin disease characterized by plaque formation. Interleukin (IL)‐23 is upregulated in psoriatic lesions and is thought to be a major regulator of the Th17 pathway in psoriasis pathogenesis. Three monoclonal antibodies targeting the IL‐23p19 subunit, guselkumab, tildrakizumab, and risankizumab, have been approved for psoriasis therapy. The balance between cytokines IL‐23 and IL‐12 can affect antitumor and pro‐tumor immune activities, and patients with psoriasis may have higher rates of cancer than the general population. Moreover, a chronic inflammatory state typical of psoriasis may induce protumorigenic effects, however, the potential risk of malignancy in patients taking these drugs remains largely unknown. This study investigated the occurrence of malignancies as suspected adverse reactions (SARs) potentially associated with IL‐23 inhibitors by analyzing real‐world data from the European EudraVigilance database. Although indicatory, these real‐world data seem to confirm the potential association between the IL‐23 inhibitors risankizumab and tildrakizumab, and the occurrence of SARs linked to cancer in patients with psoriasis and, according to a gender perspective, they show that this relationship is asymmetrically distributed between women and men, with a clear prevalence of oncologic SARs in men.


| INTRODUC TI ON
Psoriasis is a chronic inflammatory skin disease affecting approximately 3% of general population. It is characterized by a thickened and nucleated keratinocyte layer, and erythematous squamous and delimited plaques. Psoriatic lesions are the result of the interactivity of dermal infiltrates of activated dendritic cells, T-cells, and cytokines, including interferonγ, tumor necrosis factorα, interleukin (IL)-12, IL-17, and IL-23. IL-23 is upregulated in psoriatic lesions and is crucial for regulating the Th17 pathway involved in the development of psoriasis. 1 This cytokine is composed of p19 and p40 subunits binding to the receptor for IL-23 and IL-12 receptor b1, causing the triggering of pro-inflammatory Janus kinase 2, tyrosine kinase 2, and signal transducer and activator of transcription. IL-23 induces in Th17, formation of IL-17 from naive T-cells, and cellular activation by IL-17 leads to the release of pro-inflammatory cytokines. 2 Based on these findings, three monoclonal antibodies having as a target the IL-23p19 subunitguselkumab, tildrakizumab, and risankizumab have been approved.
Guselkumab is a human immunoglobulin (Ig) G1 monoclonal antibody against p19 subunit of IL-23 that inhibits IL-23 intracellular signaling.
Tildrakizumab is a humanized IgG1/x targeting the p19 (80) subunit of IL-23. Risankizumab is a selective IgG1 binding with high affinity to the IL-23 subunit p19. 3 IL-12 promotes Th1 immunity and IL-23 stimulates Th17 immunity. Increased preclinical evidence has also shown that the equilibrium between IL-12 and IL-23 is critical in tumorigenesis and that impairment of IL-12 and/or IL-2 3 signaling both promotes and inhibits tumor growth. Although the mechanisms underlying these biological activities are not fully understood and the interpretation of pre-clinical studies on the involvement of IL-12 and IL-23 in tumor biology is not univocal, clinical studies indicate IL-23 inhibitors as drugs with a good safety profile. Patients with psoriasis may have higher rates of non-melanoma skin cancer and other neoplastic diseases than the general population owing to impaired immune surveillance, immunomodulatory therapy, and chronic inflammation. 4 This can be due to chronic inflammation, distinctive features of psoriasis, and potential pro-tumorigenic effects. However, the debate on the potential risk of malignancy in patients with psoriasis taking these drugs remains unresolved to a large extent. 5 The safety and efficacy of guselkumab, risankizumab, and tildrakizumab were investigated in real-world in an observational, retrospective, multicenter cohort study that analyzed the Psoriasis Registry in Austria (PsoRA). In this study, adverse events observed were mainly non-severe infections, occurring in 11.7% of patients, showed no main differences among the three IL-23 inhibitors. 6 Other evidence obtained through the analysis of real-world data indicates that IL-23 inhibitors are generally well tolerated without any emphasis on suspected oncological adverse events. 7 This study contributes to the literature by investigating the occurrence of malignancies as suspected adverse reactions (SARs) potentially associated with IL-23 inhibitors and their distribution by sex, by analyzing real-world data contained in the database EudraVigilance.

| ME THODS
EudraVigilance is a database containing SARs linked to drugs licensed for market use in the European Union (EU). The European Medicines Agency (EMA) directs and controls the EudraVigilance. In this data bank, SARs to IL-23 inhibitors guselkumab, risankizumab, and tildrakizumab are described in individual case safety reports (ICSRs), similar to other drugs. Spontaneous signaling of SARs involves medical events that have been observed following the use of a drug, but are not necessarily caused by the same medicine. 8  The primary outcome of interest was the analysis of ICSRs reporting malignancies as SARs related to the IL-23 inhibitors guselkumab, risankizumab, and tildrakizumab in-3 years 2020-2021-2022. The odds ratio, its 95% confidence interval, and sex difference were calculated using reporting odds ratio (ROR) method. 10 Descriptive statistical analyses were performed using the statistical software SPSS version 28.0.0.0 (190).

| RE SULTS
During the years 2020-2021-2022, spontaneous signaling of 416 cases of suspected SARs were reported in EudraVigilance for IL-23 inhibitors used in the treatment of psoriasis and arthritic psoriasis.
EudraVigilance data on SARs related to IL-23 inhibitor prescription show that different typologies of cancer are represented in patients with psoriasis compared to the total number of SARs related to drugs prescribed to these patients. Oncologic SARs were 9.96%, 16.4%, and 19.3% for guselkumab, risankizumab, and tildrakizumab, respectively, in comparison to the total number of serious SARs sent for these three drugs ( Table 2). Table 2 reports the results of the disproportionality test, calculated as the odds ratio comparing each drug with the other two IL-23 inhibitors. The results indicate that the risk of suspected oncological adverse reactions to risankizumab and tildrakizumab is >1, compared to the same risk for the other two IL-23 inhibitors. This is not observed for guselkumab, which shows a minor risk compared to the other two drugs.
The disproportionality test was also applied to analyze the sex distribution of SARs among patients with psoriasis taking three   (Table 3).

| DISCUSS ION
The results of the disproportionality test, calculated as the odds ratio vs. 1.14, respectively). 14 Based on this evidence, a possible explanation for the difference observed in the EudraVigilance data in the sex distribution of oncologic SARs to IL-23 inhibitors can be supported by the pre-existing higher prevalence of cancer in male patients with psoriasis.
In conclusion, the limitations of the present study are typical of large databases containing real-world data, which have strengths in

ACK N OWLED G M ENTS
All authors have seen and approved the final version of the submitted paper and approvals have been received from any persons acknowledged or cited as having provided personal communication.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are openly available in the following public domain resource https://www.ema.europa.

E TH I C S S TATEM ENT
The authors signed an authorship responsibility form.